The invention relates to carrier liquids adapted for the production of microbubbles therein, to the use thereof as contrast medium for ultrasonic diagnostics of fluid-filled vessels or cavities of the human and animal body and to articles of manufacture comprising the carrier liquids.
It is generally known that contrast in ultrasonic diagnostics is enhanced by the presence of gas microbubbles in the liquid, such as blood, flowing through the object to be examined. For this purpose, these microbubbles can be produced outside the subject to be studied and then injected into the bloodstream. This is accomplished, for example, by vigorously shaking a fluid solution, such as a sodium chloride solution, a dye solution or previously withdrawn sample of blood, in order to produce the microbubbles; injecting the resultant microbubble-containing solution; and then conducting the ultrasonic examination as the solution passes through the vessel or cavity.
Thus, Feigenbaum et al., in their article "Identification of Ultrasound Echoes from the Left Ventricle of the Heart Through the Use of Injections of Indocyanine Green" (Circulation, Vol. XLI, April 1970), report on the production of echoes by gas microbubbles in the left ventricle of the heart, as also similarly reported by Gramiak et al. (Radiology 100 : 415-418 (1971). Such methods suffer from the limited concentrations of microbubbles produced and their lifespan after production, both of which profoundly affect the ultrasonic contrast achieved.
Another method for the generation of gas microbubbles of a specific size is described in the report "Non-Invasive Assessment of Pulmonary Hypertension Using the Bubble Ultrasonic Resonance Pressure (BURP) Method" (Report No. HR-62917-lA, April 1977, Division of Lung Diseases, National Heart, Lung and Blood Institute). In this procedure, sugar-encapsulated microbubbles are produced which have to be milled, sieved and separated according to size. The milling procedure is mandatory in order to produce material which can be injected into the body intraarterially without causing hazardous embolism.
U.S. Pat. No. 4,265,251 discloses the production of microgas bubbles with a saccharide envelope, which microbubbles can be generated with a reproducible and highly uniform size distribution, by the use of a relatively expensive and complicated apparatus. The disadvantages of this method are that the solid matrix of microbubbles, shortly prior to use, are openly intermixed with the carrier liquid, whereby sterility and absence of pyrogens are not necessarily ensured. The manufacturing process is also relatively expensive due to the complicated techniques employed. Moreover, the concentration of microbubbles which can be achieved is inherently limited.
In U.S. Pat. No. 4,276,885, a process is described for producing a liquid matrix of microbubbles encapsulated in a gelatinous membrane, using a gelable medium as the carrier for these microbubbles. For storage purposes, the microbubbles can be frozen in place by cooling and then released when required by heating. A disadvantage of this method is the fact that a thus-prepared suspension cannot be sterilized, since the microbubbles are not stable during heat sterilization and are likewise separated or destroyed by sterile filtration. Additionally, there is a risk of anaphylactic reaction with gelatin preparations.
The ultrasonic contrast medium of Application Ser. No. 207,411, filed Nov. 17, 1981, employs a solid microbubble precursor which is used to produce the microbubbles immediately prior to use, e.g., by mixing a particulate solid in a viscous aqueous carrier liquid. This process, like that of U. S. Pat. No. 4,265,251, requires the mixing of the carrier liquid prior to use with a solid in ambient air and the injection into the blood vessel of a mixture containing particulate undissolved solids.
In Abstract No. 770 of Circulation, Vol. 64, published about Oct. 7, 1981, W. J. Bommer et al., report that of the various surfactants, e.g., lecithin, glycerine, etc., which were added to blood and water samples in which microbubbles were produced, presumably in the conventional manner by shaking, those which lowered surface tension of the sample the most achieved the brightest left heart and myocardial perfusion images by contrast videodensitometry. Although we also have found that a surfactant increases the ultrasonic contrast achieved with blood and water samples, a surfactant alone does not achieve the results obtained according to this invention.
The novel ultrasonic contrast medium of this invention avoids the aforedescribed disadvantages of these other methods. We have found that significantly superior imaging is achieved in ultrasonic contrast diagnostics when a liquid vehicle is used to produce the microbubbles which contains both a surfactant (tenside) which lowers substantially the surface tension of the liquid vehicle and a viscosity-raising compound which raises substantially the viscosity of the liquid vehicle.